Since the AJCC-TNM (tumor, nodes, metastasis) melanoma classification system was based on detection of mitotic figures from a data set where mitotic figures were reported on program H&E sections, exhaustive examination of multiple levels to search only for mitotic figures is not warranted.2,72,73 The application of PHH3 in search for mitotic figures for all those melanomas is not currently part of the standard operating process at our institution. future melanoma therapy. Several publications review current melanoma-targeted therapy.17C19 Clinical response to vemurafenib therapy may be dramatic, with total shrinkage of tumor burden in patients; however, the period of response has been limited and eventual disease progression frequently occurs within months of therapy.16 Resistant mechanisms have curtailed long-term therapeutic benefit from vermurafenib therapy; thus, targeting multiple pathways or combined therapy with immune check point blockade (eg, anti-CTLA4 and anti-PD-L1) are under clinical investigation.20C23 Further review of resistant mechanisms via protective effects of insulin on melanoma cells or by activation of the PI3K/AKT pathway can be examined in a study by Chi et al.24 Future application of nanotechnology in melanoma to improve therapeutic efficacy is further reviewed by Chen et al.25 Accurate diagnosis of melanoma remains critical to further clinical management. Melanoma can demonstrate a wide range of morphologic features and may be misinterpreted as other human malignancies (eg, sarcomas, squamous cell carcinomas, Pagets disease, and lymphomas). Thus, melanoma is known as the great mimicker.26 Diagnosis of melanoma can be further Rabbit Polyclonal to Myb complicated since a subset of ambiguous melanocytic lesions may demonstrate features overlapping with melanoma and benign nevi (in particular, Spitz nevi).27 These characteristics make the histologic diagnosis of melanoma challenging for even the most experienced dermatopathologists. To help distinguish melanoma from its imitators, a variety of tissue biomarkers and ancillary techniques (eg, immunohistochemical [IHC] analysis or fluorescence in situ hybridization) are currently available. In fact, hundreds of tissue biomarkers are available in clinical laboratories for diagnosing melanoma and determining the prognosis and mutation status of this devastating skin disease. This review provides an update around the clinical applications of some of the established and emerging melanoma tissue biomarkers used at The University of Texas MD Anderson Malignancy Center. Specifically, we will review the following melanoma tissue biomarkers (Table 1) :1) melanocytic differentiation [MiTF and Sox10]; 2) vascular invasion [D2-40 and dual IHC marker with MiTF/D2-40 and Sox10/D2-40]; 3) Dot1L-IN-1 mitotic figures [PHH3, dual IHC marker with Mart-1/PHH3 and H3KT (anti-H3K79me 3T80ph)]; and 4) mutation status [anti-BRAFV600E, anti-BAP-1]. Table 1 List of selected tissue biomarkers in melanoma mutationBAP-1Ubiquitin hydrolase and enhance BRCA-1 tumor suppressionC-4 (Santa Cruz)1:150NKeratinocytesDetect the presence of mutation Open in a separate windows Abbreviations: C, cytoplasmic; IHC, immunohistochemistry; LM, lentigo maligna; LVI, lymphovascular invasion; N, nuclear. Markers of melanocytic differentiation MiTF MiTF (microphthalmia-associated transcription factor) functions in the development and differentiation of a variety of cell types, including melanocytes.28 You will find ten isoforms of MiTF, Dot1L-IN-1 with the M isoform specifically expressed in melanocytes.29 MiTF regulates the transcription of genes (eg, tyrosinase, tyrosinase-related protein 1 and 2) involved in melanin synthesis and survival of postnatal melanocytes.28,30,31 Thus, MiTF is critical for pigment synthesis and melanocyte differentiation. MiTF protein functions in the nucleus of melanocytes and can be acknowledged with antibodies directed against it. The D5 antibody recognizes human MiTF.32 The sensitivity of MiTF in melanocytic lesions exceeds 80% and is similar Dot1L-IN-1 to that of HMB45.33 In desmoplastic melanomas, however, the sensitivity of MiTF dramatically decreases to less than 55% according to some studies.32,34 The low sensitivity of MiTF in desmoplastic melanoma is comparable to that of HMB45, a marker of premelanosomal Dot1L-IN-1 glycoprotein 100. Therefore, MiTF appears to exhibit sensitivity comparable to that of HMB45 in melanocytic neoplasms. MiTF and HMB45 differ, however, in their specificity. HMB45 is usually a highly specific marker Dot1L-IN-1 with greater than 97% specificity for melanocytic differentiation.35,36 In contrast, the specificity of MiTF in melanocytic lesions is less, and the widespread use of this biomarker alone in evaluating melanocytic lesions is an important pitfall. MiTF has been shown to spotlight cells other than melanocytes and nonmelanocytic neoplasms. In particular, MiTF reactivity can be seen in macrophages, fibroblasts, and mast cells and in a variety of spindle cell tumors.
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